The overall goal of this program has been to understand the genetic basis of human leukemias, and to develop novel therapeutic approaches based on these insights. During the past 9 years of the program, we have made major strides in this regard, including characterization of mutant FLT3 alleles in human leukemias in cell culture and murine models of leukemia, developing and testing small molecule tyrosine kinase inhibitors as therapeutic agents, and bringing these small molecule inhibitors forward into Phase I and Phase II clinical trials. During the next proposed 5-year study period we will build on these successes, and expand our efforts into new therapeutic venues based on recent findings and discoveries among members of the Program Project. In Project 1, Dr. Griffin will focus on improving the efficacy of FLT3 inhibitors by using "combination targeted therapy", by evaluating the mechanisms of clinical resistance to FLT3 inhibitors, and initiating efforts to develop small molecule tyrosine kinase inhibitors of JAK2V617F as therapeutic agents in the myeloproliferative diseases. Dr. Gilliland will focus in Project 2, on understanding the relative contributions of FLT3-ITD and FLT3 activation loop mutations to the pathogenesis of myeloid and lymphoid leukemias, respectively, using knock-in alleles of these FLT3 mutants. He will focus continued effort on understanding cooperation of these alleles with other leukemia associated alleles, such as PML-RARa, C/EBPa, MLL and AML1-ETO, and in developing accurate murine models of JAK2V617F MPD for testing inhibitors developed in Project 1. In Project 3, Dr. Tenen will continue efforts to better understand the contributions of mutant hematopoietic transcription factors in pathogenesis of leukemia, including PML-RARa, C/EBPa, and PU.1. Dr. Armstrong is a new addition to the Program, and will study the role of MLL fusion genes in leukemogenesis, alone and in cooperation with mutations of C/EBPa based on recent data suggesting that these alleles cooperate, and will further characterize leukemia stem cells in murine models of MLL-AF4 and MLL-AF9 mediated leukemias. Dr. Stone will continue to lead the clinical translational component of this Program in Project 5, and will initially focus on continued development of FLT3 inhibitors in "up-front" trials with induction chemotherapy to treat AML, and to implement novel therapies as they are developed and validated in the other projects, including, for example, JAK2 inhibitors for treatment of MPD. These Projects will each be supported by the Tissue Banking and Flow Cytometry Core B run by Dr. Jerome Ritz, and by close interactions with the Biostatistical Core C run by Dr. Donna Neuberg in all aspects of clinical trial design in human and murine model systems. Collectively, the Program will build on previous strengths and a demonstrated track record of success in the pipeline of developing novel therapies that begins with target gene discovery, development of preclinical models of transformation, development and testing of molecularly targeted therapies, and clinical implementation in Phase I and Phase II trials.